This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Brain disease caused by the human AIDS virus (termed HIV) has been linked to HIV's ability to grow well in microglia (MG), cells that reside in the central nervous system (CNS) and originate from bone marrow. We postulate that the ability of an AIDS virus to replicate efficiently in MG represents a hallmark of AIDS virus-associated brain disease. We further postulate that the envelope gene of HIV that has been adapted to cultured human MG will confer the ability to cause brain disease to a simian-human immunodeficiency virus (SHIV) that contains this gene. SHIVs are hybrid viruses that are part SIV and part HIV, including the HIV envelope gene. We have constructed SHIV-Bo159N4, which contains the envelope gene of a primary HIV strain that had been adapted in cultured human MG. Our new virus replicated well in the blood cells of all monkeys tested, and like the original HIV strain from we had cloned the envelope gene, SHIV-Bo159N4 enters cells through a molecule called CCR5 and forms giant cells containing many nuclei. We have already inoculated several monkeys with SHIV-Bo159N4 and are now testing whether SHIV neurovirulence can be increased by serial passage through infected MG from monkeys with high CSF viral loads to new recipients. Our new strategy involves simultaneous ablation of CD8+ cells as well as B cells in the recipients to augment viral replication in the blood and CNS. Our SHIV-infected monkeys are being followed prospectively for viral, hematological and neurological parameters.